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  • The EMBO Journal (2007) 26, 3144 - 3156
  • doi:10.1038/sj.emboj.7601745

Published online: 7 June 2007

Drosophila Omi, a mitochondrial-localized IAP antagonist and proapoptotic serine protease

Madhavi Challa1,2,a, Srinivas Malladi1,2,a, Brett J Pellock3, Douglas Dresnek3, Shankar Varadarajan1,2, Y Whitney Yin2,4, Kristin White3 and Shawn B Bratton1,2

  1. Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA
  2. Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA
  3. Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
  4. Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX, USA

Correspondence to:

Shawn B Bratton, Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, 1 University Station A1915, 2409 University Avenue, Austin, TX 78712-0125, USA. Tel.: +1 512 471 1735; Fax: +1 512 471 5002; E-mail: sbbratton@mail.utexas.edu

aThese authors contributed equally to this work

Received 31 January 2007; Accepted 10 May 2007

Although essential in mammals, in flies the importance of mitochondrial outer membrane permeabilization for apoptosis remains highly controversial. Herein, we demonstrate that Drosophila Omi (dOmi), a fly homologue of the serine protease Omi/HtrA2, is a developmentally regulated mitochondrial intermembrane space protein that undergoes processive cleavage, in situ, to generate two distinct inhibitor of apoptosis (IAP) binding motifs. Depending upon the proapoptotic stimulus, mature dOmi is then differentially released into the cytosol, where it binds selectively to the baculovirus IAP repeat 2 (BIR2) domain in Drosophila IAP1 (DIAP1) and displaces the initiator caspase DRONC. This interaction alone, however, is insufficient to promote apoptosis, as dOmi fails to displace the effector caspase DrICE from the BIR1 domain in DIAP1. Rather, dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 and induces apoptosis both in cultured cells and in the developing fly eye. In summary, we demonstrate for the first time in flies that mitochondrial permeabilization not only occurs during apoptosis but also results in the release of a bona fide proapoptotic protein.

  • Keywords:

    • apoptosis,
    • DIAP1,
    • dOmi,
    • DRONC,
    • Drosophila